Understanding the development and function of the brain requires the elucidation of mechanisms underlying the generation of an extremely large number of neurons with unique identities. Moreover, the multitude of distinct neurons ultimately must connect to each other in specific patterns. The olfactory system provides an excellent model system for investigating these questions because the 1,000 olfactory receptor genes serve as molecular markers for functionally distinct subsets of neurons. Our preliminary studies indicate that a hierarchy of controls operates on the family of olfactory receptor genes, such that a given olfactory neuron expresses only one of the thousand possible genes. One mechanism involved in regulating olfactory receptor gene expression is allelic inactivation (only one of two alleles is expressed). Based on these studies, the aims of this proposal are to elucidate mechanisms underlying olfactory receptor gene regulation and allelic inactivation: 1. To determine if DNA rearrangement plays a role in the choice of which olfactory receptor is expressed. 2. To define the cis-acting DNA elements involved in regulating olfactory receptor genes. 3. To further characterize allelic inactivation and to identify its underlying molecular mechanisms. The potential role of rearrangement will be addressed in molecular studies of purified olfactory neurons expressing a given receptor and in cell lines derived from the olfactory neuroepithelium. Once cells which have chosen a given receptor are isolated, the genomic DNA will be analyzed to look for DNA rearrangement. Independent of the question of rearrangement, we wish to understand elements of control. We will use yeast artificial chromosomes (YACs) to map the loci encoding olfactory receptors. Cis acting DNA elements involved in receptor gene choice will be defined in transgenic mouse experiments. Experiments to characterize allelic inactivation will involve analyses of transcription and DNA replication in cell lines and transgenic mice. These studies will elucidate mechanisms through which gene regulation leads to the remarkable generation of neuronal diversity in the brain, and will be of value in understanding disorders of brain function. Moreover, mammalian olfactory neurons regenerate throughout the life of the organism. Thus, understanding the gene expression mechanisms used by these neurons is of particular relevance to understanding neurodevelopmental disorders.
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